Molecular Neurodegeneration最新文献

{"title":"Inflammatory signaling differentially changes chromatin accessibility and gene expression of the PD- associated kinase LRRK2 between human and mice.","authors":"Alexandra Beilina, Jae-Hyeon Park, Natalie Landeck, Ruth Chia, Jinhui Ding, Xylena Reed, Hannah Bailey, Changyoun Kim, Alice Kaganovich, Dominic J Acri, Janet Brooks, Alexandra Mann, Kareem A Zaghloul, Elise Marsan, J Raphael Gibbs, Alex DeCasien, Mark R Cookson","doi":"10.1186/s13024-026-00938-0","DOIUrl":"10.1186/s13024-026-00938-0","url":null,"abstract":"<p><p>The genomic locus that encodes the Leucine-rich repeat kinase 2 (LRRK2) gene is highly pleiotropic and associated with Parkinson’s disease (PD). Coding variants associated with risk of PD act as gain of function kinase mutations increasing phosphorylation of RAB substrates, and non-coding variants in the promoter region of LRRK2 increase expression of the gene, notably in immune cells. If regulation of LRRK2 expression is a causal contributor to PD, it is important to understand the mechanism(s) by which LRRK2 is regulated, particularly in the context of inflammation. Here, we show that interferon-ɣ exposure induces robust LRRK2 activation in human iPSC-derived microglia through signaling of the Janus-activated Kinase complex to phosphorylate STAT1, which then binds to the LRRK2 promoter and is associated with remodeling of chromatin structure in this genomic locus. Additional regulatory mechanisms include the stress-induced transcription factor and long non-coding RNA encoded at the same locus, resulting in increased LRRK2 mRNA levels. We also show evidence of the same effect in acutely cultured human brain slices. While we were unable to demonstrate any induction of Lrrk2 mRNA in the mouse brain, the introduction of a human bacterial artificial chromosome transgene into the mouse genome recapitulated sensitivity to interferon-ɣ in microglia. A comparative genomic analysis across mammals suggests that these species differences are driven by regulatory regions upstream of LRRK2 that are specific to anthropoid primates. These results demonstrate that there are differences between species in how genes associated with human diseases are regulated and provide important information that should be incorporated in disease modeling.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147481187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PU.1: the conductor of Alzheimer's symphony.","authors":"Chunli Sun,Qianjin Liu","doi":"10.1186/s13024-026-00937-1","DOIUrl":"https://doi.org/10.1186/s13024-026-00937-1","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"30 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered trafficking of Kv1-Kvβ2 leads to neuronal hyperexcitability and memory deficits in amyloid-β pathology.","authors":"Young-Sin Cho,Seo-Hyun Kim,Shin-Hyeon Ryu,Chaelin Chung,Nahyun Lee,Namhoon Kim,Muhah Jeong,Youngwon Kim,Jimin Gwak,Se-Young Choi,Takaomi Saido,Yong-Keun Jung","doi":"10.1186/s13024-026-00936-2","DOIUrl":"https://doi.org/10.1186/s13024-026-00936-2","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"67 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systems biology of Alzheimer's Disease: a scoping review of key pathways and mechanisms.","authors":"Paula J Bice, Kwangsik Nho, Nilüfer Ertekin-Taner, Andrew J Saykin","doi":"10.1186/s13024-026-00934-4","DOIUrl":"10.1186/s13024-026-00934-4","url":null,"abstract":"<p><p>Alzheimer’s Disease (AD) is a progressive and ultimately fatal neurodegenerative disorder, representing the most common form of dementia and affecting nearly 7 million people in the United States. For over a century, research has centered on hallmark AD pathologies—extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau (pTau). While these mechanisms remain central to our understanding of the Disease, the underlying molecular events and broader biological pathways driving AD are still not fully understood. Precision medicine for AD and related dementias (ADRD) requires a comprehensive understanding of neurodegenerative Disease through pathophysiologic biomarkers for early detection, prediction of progression, and for evaluating response to treatment. Systems biology provides a powerful framework for this effort, leveraging multi-omics for biomarker discovery and elucidation of critical Disease pathways. The purpose of this scoping review is to identify and inform the field on key pathways being intensively investigated in AD/ADRD, including hallmark pathology, proteostasis, inflammation, oxidative stress, glucose metabolism, lipid dysregulation, neurotransmitter systems, synaptic integrity, neurogenesis, co-pathology- and sex-related pathways. Finally emerging biomarkers, tools and strategies for discovery and analysis are discussed, emphasizing advances related to the emerging precision medicine for AD.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13032323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147276785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired nucleocytoplasmic transport in SOD1-mediated ALS.","authors":"Shirel Argueti-Ostrovsky, Su Min Lim, Olubankole A Arogundade, Sandra Diaz-Garcia, Gulshan Yunisova, Alex Meng, Anita Hermann, Kailee Ong, Ekaterina Eremenko, Mariana Bravo-Hernandez, Shawn P Driscoll, Chao-Zong Lee, Xin Jiang, Alexandra Stavsky, Shir Barel, Tom Shani, Joy Kahn, Samuel L Pfaff, Alon Monsonego, Martin Marsala, John Ravits, Clotilde Lagier-Tourenne, Adrian Israelson","doi":"10.1186/s13024-026-00930-8","DOIUrl":"10.1186/s13024-026-00930-8","url":null,"abstract":"<p><p>BACKGROUND: Impaired nucleocytoplasmic transport (NCT) has emerged as a shared pathogenic mechanism in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in the gene encoding superoxide dismutase 1 (SOD1) account for approximately 20% of familial ALS cases, the impact of mutant SOD1 accumulation on the NCT remains unclear. METHODS: Utilizing in vitro and in vivo models, patient-derived fibroblasts, and postmortem spinal cord tissues from ALS patients with SOD1 mutations, we determined the effects of mutant SOD1 on NCT dynamics, nuclear morphology and cellular localization of transport receptors and nuclear pore components. RESULTS: Mutant SOD1 disrupts nuclear import and export trafficking, causing cytosolic accumulation of key transport regulators such as RanGAP1 and exportin 1 (XPO1). Mutant SOD1 also lowers the abundance of FG-Nups at the nuclear pore without altering nuclear circularity. Abnormal accumulation of NCT components was identified in Iba1-positive microglia, indicating a previously overlooked, non-cell-autonomous contribution to disease pathogenesis. Importantly, AAV-mediated reduction of mutant SOD1 in transgenic mice restored nuclear XPO1 localization, underscoring the causal role of mutant SOD1 in NCT abnormalities. Finally, comparable NCT perturbations were observed in patient-derived fibroblasts and in post-mortem spinal cord tissues from individuals with SOD1-ALS. CONCLUSIONS: Our results implicate NCT disruption as a shared disease mechanism between SOD1-mediated ALS and other familial and sporadic forms of ALS, adding support for targeting this pathway as an attractive therapeutic strategy in this fatal disease.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":"14"},"PeriodicalIF":19.6,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The functional role of glial cells in the pathologic brain as reviewed by Alois Alzheimer in 1910.","authors":"Helmut Kettenmann, Hans Lassmann, Bilge Ugursu, Xianyuan Xiang","doi":"10.1186/s13024-026-00933-5","DOIUrl":"10.1186/s13024-026-00933-5","url":null,"abstract":"<p><p>Alois Alzheimer is known for the clinical diagnosis and neuropathological analysis of the neurodegenerative disease named after him. Yet, a less celebrated but equally fundamental contribution lies in his monograph, “Contributions to the knowledge of the pathologic neuroglia and their relationship to degenerative processes in the nervous tissue.” This work, now translated, meticulously details the dynamic role of glial cells in brain pathology, a paradigm-shifting concept for its time. Alzheimer applied then-novel staining techniques -including adaptations of Scharlach red and Mallory hematoxylin- to visualize lipids and protoplasmic degradation in post-mortem human brains. These approaches revealed striking changes in the glial network across disorders ranging from stroke and trauma to multiple sclerosis, syphilis-related dementia, various forms of neurodegeneration, and schizophrenia. He documented the appearance of two novel glial forms, which he termed “ameboid glia” and “glial granule cells”, involved in the phagocytosis of “fatty matter” and “lipoid substances” from degenerating nervous tissue. He also documented “neuronophagia,” where glial cells appeared to directly interact with and “dissolve” damaged neurons. This work laid the conceptual groundwork for modern neuroscience. We now recognize Alzheimer’s “ameboid glia” as the earliest documented observations of activated microglia and astrocytes, and his descriptions of glia’s engagement with cellular damage provided the first evidence for what we now call neuroinflammation. His methodical approach and detailed observations proved that glial cells are not passive bystanders but central, active players that sense, respond to, and shape the course of brain diseases. The English translation and the original German text can be found in the attachment.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13005332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting tau in Alzheimer's Disease: rationale, approach and challenges.","authors":"Aram Aslanyan, Martha S Foiani, Tatiana A Giovannucci, Eric McDade, Karen E Duff, Catherine J Mummery, Michael Schöll, Kristin R Wildsmith, Ross W Paterson","doi":"10.1186/s13024-026-00925-5","DOIUrl":"10.1186/s13024-026-00925-5","url":null,"abstract":"<p><p>Alzheimer’s Disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia characterised by the accumulation of beta amyloid (Aβ) plaques and neurofibrillary tangles (NFT). Several monoclonal antibodies against amyloid in early AD have shown the utility of reducing brain amyloid in large phase 3 studies, resulting in modest clinical benefit. To further slow, or even halt disease progression, targeting additional pathobiological pathways is likely to be necessary. In this review, we aim to appraise the scientific rationale for targeting tau in AD. The burden of tau pathology is correlated with disease severity and its role in AD progression is complex, involving synapse dysfunction, neuronal loss, neuroinflammation and autophagy impairment. Evidence suggests that hypersecretion, post-translational modifications and aggregation propensity, dependent and independent of amyloid, are also linked to neurodegeneration. We review the therapeutic agents in development including tau synthesis modifiers, active and passive immunotherapies, post-translational modifiers and aggregation inhibitors. Finally, we consider the available biomarker tools for patient selection and drug effectiveness evaluation, and we identify key knowledge gaps that future novel biomarkers might address to make clinical trials of tau therapies more likely to succeed.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12973685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid alterations in hereditary peripheral neuropathies: common mechanisms in disease heterogeneity?","authors":"Koen Kuipers, Sam Vanherle, Kirsten Poelmans, Esther Wolfs, Jeroen Bogie, Tim Vangansewinkel","doi":"10.1186/s13024-026-00932-6","DOIUrl":"10.1186/s13024-026-00932-6","url":null,"abstract":"<p><p>While the impact of lipid alterations on central nervous system disorders is well-studied, increasing evidence indicates that lipids also play an important role in the pathology of hereditary peripheral neuropathies (HPN). It is becoming clear that Schwann cells and neurons in peripheral nerves heavily depend on lipids for membrane interactions, (sub)cellular signalling, and the formation of myelin sheaths. In support of this notion, disturbances in the level and composition of lipid classes, including phospholipids, sphingolipids and cholesterol, perturb normal functioning of peripheral nerves. Intriguingly, lipid disturbances seem to be a common denominator within the heterogeneous group of HPN, with hindrances in cholesterol and sphingolipid metabolism primarily influencing Schwann cell and neuron homeostasis, respectively. In this review, we provide an overview of lipid disturbances in various HPN with the goal of finding main commonalities between the different diseases and to identify potential novel treatment strategies.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12964804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two lysosomal genes ATP13A2 and GBA1 interact to drive neurodegeneration.","authors":"Mingxue Gu,Jinghan Zhao,Mingxi Deng,Guang Lin,Xueyang Pan,Wenwen Lin,Mengqi Ma,Jinyong Kim,Seul Kee Byeon,Akhilesh Pandey,Lara M Lange,Chad A Shaw,Jonggeol Kim,Joanne Trinh,Christine Klein,Oguz Kanca,Joshua M Shulman,Hugo J Bellen","doi":"10.1186/s13024-025-00923-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00923-z","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"1 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146089076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics insights into GBA1-associated Parkinson's disease: interplay of genomics, transcriptomics, proteomics, and lipidomics.","authors":"Yang Ni,Huaibin Cai,Yaping Shao,Weidong Le","doi":"10.1186/s13024-026-00931-7","DOIUrl":"https://doi.org/10.1186/s13024-026-00931-7","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"103 1","pages":"6"},"PeriodicalIF":15.1,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146073263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}